One of the greatest challenges facing cancer chemotherapy is the dose-limiting toxicity to normal healthy cells that occurs during the process of killing cancerous cells. Nanotechnology represents a new and enabling platform that promises to provide a broad range of novel uses and improved technologies for biomedical applications based on the unique physiochemical properties inherent in nanomaterials. Nanoparticles, comparable in size to naturally occurring biological molecules, are currently being investigated for use in cancer applications. However, none of the currently developed nanotechnology treatments are based on the inherent toxicity of the nanoparticles themselves, as the toxicity of most nanomaterials has not been reported to selectively kill cancer. Our proof-of-concept experiments have recently demonstrated that carefully engineered ZnO nanoparticles can preferentially kill cancerous T cells (28-35 times) compared to normal quiescent T cells. The ability of identical concentrations of these nanoparticles to kill cancerous cells while leaving normal body cells intact and immunity uncompromised is an attractive approach. The objective of this project is to obtain a better understanding of the mechanisms by which ZnO and other similar oxide nanoparticles kill cancer cells so that their toxicity and selectivity may be further improved by engineering design. Studies proposed in specific aim 1 will verify that ZnO nanoparticles preferentially kill a variety of hematological malignancies while sparing normal body cells, and will determine if similar responses are observed for SnO2 and NiO nanoparticles. Understanding how ZnO nanoparticles induce cell selective toxicity will be addressed in specific aim 2 to identify mechanism(s) of nanoparticle-induced reactive oxygen species generation and inter-relationships between nanoparticle uptake, cell cycle status, and susceptibility to nanoparticle-induced death. Specific aim 3 will determine the extent to which alterations in nanoparticle electrostatics, antibody functionalization, and iron-doping to promote greater intracellular reactive oxygen species generation lead to improved cancer cell specificity and cytotoxic action. Using ZnO nanoparticles systems identified in aim 3 showing the greatest cancer cell selectivity, in vivo toxicity and anti-tumor activity experiments will be performed using a murine leukemia model in specific aim 4. This project seeks to evaluate the potential utility of metal oxide nanoparticles for cancer applications by understanding the molecular basis for their cell selective cytotoxic properties, and then using this information to guide improvements in their chemical synthesis to improve nanoparticle therapeutic potential. PUBLIC HEALTH RELEVANCE: New improvements in cancer treatments are urgently needed and nanotechnology, which is the integration of nanomaterials science and biology, offers promising new opportunities. It is the very small size of nanoparticles, comparable in size to naturally occurring biomolecules, that makes them particularly attractive for novel biomedical uses because they frequently display new physical, chemical and biological properties that can be used to manipulate cell responses. Our published experiments have shown that ZnO nanoparticles can preferentially kill cancerous leukemia and lymphoma cells while leaving normal body cells intact. The goal of this project is determine how effective these nanoparticles are at killing hematological malignancies while sparing normal body cells and tissues, and to obtain a better understanding of the killing mechanisms so that their toxicity and cancer cell selectivity may be even further improved by engineering design to make them attractive new anti-cancer agents.